Synthesis of 7-oxopyrrolo-[3,2-d]pyrimidine 5-oxides by the rearrangement of 6-alkynyl-5-nitropyrimidines

Article abstract of DOI:10.1007/s10593-005-0074-y

A method is proposed for the synthesis of 6-substituted 4-amino-7-oxopyrrolo[2,3-d]pyrimidine 5-oxides which includes a Sonogashira reaction of 4-amino-6-chloro-5-nitropyrimidine with terminal alkynes and subsequent rearrangement of the 6-alkynyl-5-nitrop

Full text of DOI:10.1007/s10593-005-0074-y

Chemistry of Heterocyclic Compounds, Vol. 40, No. 10, 2004
SYNTHESIS OF 7-OXOPYRROLO-
[
3,2-d]PYRIMIDINE 5-OXIDES BY THE
REARRANGEMENT OF 6-ALKYNYL-
5-NITROPYRIMIDINES
S. Tumkevicius, I. Susvilo, and A. Brukstus
A method is proposed for the synthesis of 6-substituted 4-amino-7-oxopyrrolo[2,3-d]pyrimidine 5-oxides
which includes a Sonogashira reaction of 4-amino-6-chloro-5-nitropyrimidine with terminal alkynes and
subsequent rearrangement of the 6-alkynyl-5-nitropyrimidines obtained.
Keywords: alkynes, nitropyrimidines, palladium, pyrrolo[3,2-d]pyrimidines, catalysis, rearrangement.
One of the routes for the synthesis of the pyrrolo[3,2-d]pyrimidine heterocyclic system involves the
formation of a pyrrole ring by an intramolecular cyclization of the corresponding substituted pyrimidine.
Analysis of the literature has shown that 5-aminopyrimidines are most frequently chosen as starting materials in
achieving this goal [1-8]. There are only a few reports in the literature concerning the synthesis of
pyrrolo[3,2-d]pyrimidines from 6-alkynylpyrimidines [9] and 5-nitropyrimidines [10-15]. The latter usually form
pyrrolopyrimidines under reductive cyclization conditions. However, according to our study of the literature, the
synthesis of pyrrolo[3,2-d]pyrimidines from 5-nitropyrimidines having alkyl substituents in the position 6 has
not been reported. We have recently published a preliminary report of the possible synthesis of pyrrolo[3,2-
d]pyrimidine 5-oxides by the rearrangement of certain 1-(4-amino-5-nitro-6-pyrimidinyl)-2-arylethynes in
pyridine solution [16]. In the current work we continue the investigation to provide additional data for the
synthesis of 7-oxo-7H-pyrrolo[3,2-d]pyrimidine 5-oxides. These compounds are aza analogs of isatogens [17-
1
9] and are of interest as materials which bind radicals in a biological medium.
The readily prepared 4-amino-6-chloro-5-nitropyrimidine (1) [10] was chosen as the starting material in
the synthesis. Investigation of the cross conjugation reaction of compound 1 with terminal alkynes in the
presence of PdCl (PPh ) and CuI catalysts in triethylamine has shown that the best results are achieved by
2
3 2
carrying out this reaction with a small excess of the appropriate acetylene at 40°C. The compounds 2a-e are
formed in 68-89% yields.
Study of the properties of the alkynylpyrimidines has shown that, when heated for a short time (15 min)
in pyridine, they undergo a rearrangement to form the 6-substituted 4-amino-7-oxopyrrolo[2,3-d]pyrimidine
5
-oxides 3a-d (method A).
The yields of compounds 3a-d are 87-95%. Only the reaction of compound 2e occurs differently. In this
case a complex mixture of products is formed along with tarring of the reaction mixture and the expected
product could not be separated. The reason could be the instability of compound 2e, which is partially
decomposed even when attempts are made to purify it using column chromatography or crystallization.
_
_________________________________________________________________________________________
Organic Chemistry Department, Vilnius University, Vilnius LT-03225, Lithuania; e-mail:
sigitas.tumkevicius@chf.vu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10.
pp. 1546-1550, October, 2004. Original article submitted July 7, 2004.
0
009-3122/04/4010-1335©2004 Springer Science+Business Media, Inc.
1335

_
O
NH2
NH2
NO2
Cl
1.
R , Pd cat., CuI
. C H N, 40°C
N+
N
N
R
2
5
5
N
N
O
3
a–d
1
R , Pd cat., CuI
0°C
4
C H N, 40°C
5
5
NH2
NO2
N
N
R
2
a–e
a R = Bu, b R = Ph, c R = 4-MeC H , d R = 4-F-C H , e R = SiMe
3
6
4
6
4
In view of the fact that the preparation of the alkynylpyrimidines and the conversion of compounds 2a-e
to the pyrrolo[3,2-d]pyrimidine 5-oxides 3a-e occur in the presence of a tertiary amine base it seemed
appropriate to us to study the possible preparation of compound 3 in a single stage, directly from the
chloropyrimidine 1. It was found that the triethylamine used in the cross conjugation stage does not cause the
rearrangement of the alkynylpyrimidines formed. At the reflux temperature of triethylamine only a tarring of the
reaction mixture occurs which markedly lowers the yields of the alkynylpyrimidines and hinders their
separation. The formation of compound 3 was not observed. Upon addition of pyridine to the reaction mixture
and carrying out the reaction at 40°C the 6-substituted 7-oxopyrrolo[3,2-d]pyrimidine 5-oxides 3a-c are formed
(
method B). The yields of compounds 3a-c as obtained using method B were less than the overall yields via the
synthesis in the two stage method A. However, method B has the advantage that it avoids the procedure of the
separation and purification of the intermediate alkynylpyrimidines.
The data obtained shows that pyridine can serve as catalyst in the rearrangement of the 6-alkynyl-5-
nitropyrimidines to the corresponding 7-oxopyrrolo[2,3-d]pyrimidine 5-oxides. Evidently the pyridine adds to
the triple bond and activates the alkyne. Subsequent nucleophilic attack on the oxygen of the nitro group leads to
formation of an isoxazole derivative which then rearranges to the 7-oxopyrrolo[2,3-d]pyrimidine 5-oxide.
_
_
_
O
N
O
N
NH2
NH2
NH2
N
O
+
+
N
N
O
N
N
O
O
_
N
N
R
+
R
2
N
R
N +
.
.
N
NH2
N
O
_
O
N
NH2
N
O
N
NH2
N
_
N
R
N
O
N
R
3
+
+
N
N
– C H N
5 5
N
_
N +
R
O
O
1
336

A catalytic role for the pyridine was also noted in a study of the photochemical isomerization of
-nitrotolanes [20]. It was also shown that electron-acceptor substituents stabilize the carbanion formed and
2
facilitate the reaction. In our case the electron deficient pyrimidine ring is such a group. It evidently also dictates
that the 6-alkynyl-5-nitropyrimidines 2 readily undergo rearrangement to the 7-oxopyrrolo[2,3-d]pyrimidine
5
-oxides 3 in the absence of UV irradiation.
We therefore propose a novel and convenient method for the synthesis of compounds of type 3 from
-alkynyl-5-nitropyrimidines which are readily prepared by a Sonogashira reaction of 6-chloro-5-
6
nitropyrimidine with terminal alkynes.
EXPERIMENTAL
IR spectra were recorded using vaseline oil on an FT-IR Spectrum BX II spectrometer (Perkin-Elmer).
H NMR spectra were taken on a Tesla 587A (80 MHz) or a Varian INOVA (300 MHz) spectrometer using
1
TMS as internal standard. The course of the reaction and the purity of the compounds obtained were monitored
using TLC on Alufol Silica Gel 60 F254 plates (Merck).
The characteristics of the compounds 2b-d, 3b-d are given in [16].
1
-(4-Amino-5-nitro-6-pyrimidinyl)-2-substituted Acetylenes 2a-e (General Method). A mixture of
compound 1 (0.2 g, 1.16 mmol), PdCl (PPh ) (0.015 g, 0.021 mmol), and CuI (1.98 mg, 0.0105 mmol) in dry
2
3 2
triethylamine (5 ml) was stirred in an argon atmosphere for 1-3 min. The corresponding acetylene (1.25 mmol)
was added and the reaction mixture was stirred for 2-3 h at 40°C. After cooling, the precipitate was filtered off
and recrystallized (in the case of compounds 2a-d) or washed with water (in the case of compound 2e) to give
the compounds 2a-e.
-
1
Compound 2a. Yield 70%; mp 159°C (octane). IR spectrum, ν, cm : 3382, 3220 (NH ), 2209 (C≡C),
2
1
1
569 (NO ). H NMR spectrum (CDCl ), δ, ppm (J, Hz): 0.98 (3H, t, J = 5.6, CH ); 1.56 (4H, m,
CH CH CH CH ); 2.85 (2H, t, J = 5.6, CH ); 7.88 (2H, br. s, NH ); 8.74 (1H, s, H-2). C NMR spectrum
2
3
3
1
3
2
2
2
3
2
2
(
CD Cl ): 13.48, 21.01, 22.03, 37.49, 84.47, 87.06, 122.48, 144.91, 162.82, 167.91. Found, %: C 54.48; H 5.42;
2 2
N 25.38. C H N O . Calculated, %: C 54.54; H 5.49; N 25.44.
1
0
12
4
2
Compound 2b [16]. Yield 75%. Compound 2c [16]. Yield 89%. Compound 2d [16]. Yield 68%.
-
1
Compound 2e. Yield 86%; mp 149-150°C. IR spectrum, ν, cm : 3344, 3198 (NH ), 2215 (C≡C), 1568
2
1
(
NO ). H NMR spectrum (DMSO-d ), δ, ppm: 0.26 (9H, s, Si(CH ) ); 8.45 (1H, s, H-2); 9.02 (2H, br. s, NH ).
2
6
3 3
2
6
-Substituted 4-Amino-7-oxo-7H-pyrrolo[3,2-d]pyrimidine 5-Oxides 3a-d. A. A solution of the
corresponding compounds 2a-d (1 mmol) in anhydrous pyridine (5 ml) was refluxed for 15 min. After cooling to
room temperature the precipitate was filtered off and the filtrate was concentrated at reduced pressure. The
precipitate formed was combined with that obtained previously and recrystallized to give compounds 3a-d.
B. A mixture of compound 1 (0.2 g, 1.16 mmol), PdCl (PPh ) (0.015 g, 0.021 mmol), CuI (1.98 mg,
2
3 2
0
.0105 mmol), and dry triethylamine (5 ml) was stirred under an argon atmosphere for 1-3 min. The
corresponding acetylene (1.25 mmol) was added and the reaction mixture was stirred for 30 min at 40°C.
Pyridine (0.5 ml) was added and stirring was continued for a further 2-24 h. The reaction mixture was cooled
and the precipitate filtered off and recrystallized to give compounds 3a-c.
Compound 3a. Yield 92% (method A), 36% (method B, reaction time 24 h); mp 223°C (benzene).
-
1
1
IR spectrum, ν, cm : 3341, 3299 (NH ), 1736 (CO), 1348 (NO). H NMR spectrum (DMSO-d ), δ, pm (J, Hz):
2
6
1
.05 (3H, t, J = 5.6, CH ); 1.51 (4H, m, CH CH CH CH ); 2.99 (2H, t, J = 5.6, CH ); 6.80 (1H, br. s, NH); 7.75
3 2 2 2 3 2
1
3
(
1H, br. s, NH); 8.10 (1H, s, H-2). C NMR spectrum (DMSO-d ), δ, ppm: 13.28, 22.01, 22.63, 29.75,122.45,
6
1
36.96, 150.28, 154.89, 166.98, 187.93. Found, %: C 54.45; H 5.68; N 25.29. C H N O . Calculated, %:
10 12 4 2
C 54.54; H 5.49; N 25.44.
Compound 3b. Yield 95% (method A) [16], 49% (method B, reaction time 2 h).
Compound 3c. Yield 90% (method A) [16], 38% (method B, reaction time 4 h).
1
337

This work was carried out with the financial support of the Lithuanian Fund for Science and Education,
grant No. T-04220.
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